Alzheimer's dementia (AD) is the most common form of dementia and affects around 20 million people worldwide. The main pathological feature of AD is the formation of senile or amyloid plaques, consisting of Aβ peptide (amyloid-beta peptide, A-Beta peptide), and neurofibrillary deposits of the tau protein. The amyloid cascade hypothesis came about in the 1990s and postulates that the deposition of Aβ in the form of plaques triggers the symptoms of the disease. More recent studies indicate that smaller, freely diffusible Aβ oligomers are more toxic than the Aβ fibrils deposited in the plaques. According to recent work, the plaques can be regarded as a reservoir for oligomeric Aβ, which is colocalized with the destruction of synapses and neurons. Aβ peptide is created by the activities of at least two different proteases from a precursor protein, the “Amyloid Precursor Protein” (APP). This is located in the cell wall of neurons. During the proteolytic breakdown of APP and by subsequent modification, Aβ fragments of varying lengths and types are produced. After digestion by gamma-secretase, Aβ peptides of varying lengths are formed, for example Aβ 1-42, Aβ 1-40, and so on. These species differ in their tendency to aggregate. In addition, it is known that some of the Aβ species found in the human brain can no longer be detected as the original peptide but rather as truncated AβpE3-x. AβpE3-x denotes amino-terminal truncated peptides, the free glutamic acid residue of which lies in position 3 in the form of cyclized pyroglutamate. The C-terminus is variable, for example AβpE3-40, AβpE3-42, and so on. AβpE3-x, especially AβpE3-42, is largely detected in the center of amyloid plaques and is much more likely to aggregate and much more toxic to cells than non-amino-terminal truncated and modified Aβ.
There is therefore a need for substances that reduce the quantity of toxic Aβ oligomers and/or truncated and modified Aβ species.
To date, no medicament exists that acts on the cause of Alzheimer's dementia. The medicaments used to date are at best able to alleviate some symptoms, but are unable to slow, far less stop, the progress of the disease.
Disadvantageously it has, therefore, been possible to treat only the symptoms of Alzheimer's dementia to date. There are no approved medicaments that can stop or reverse the disease processes. Most of the substances researched for treating Alzheimer's dementia focus on extracellular Aβ but do not focus specifically on soluble Aβ oligomers or on truncated Aβ species such as AβpE3-42 that are likely to aggregate. However, this is precisely what is required in order to be able to stop the disease process in the early stages.
Furthermore, there is to date no way of diagnosing Alzheimer's dementia before the appearance of symptoms. At present Alzheimer's dementias are detected mainly through neuropsychological tests carried out on a person already suffering from dementia symptoms. Other diseases (traumas) can moreover be ruled out by different investigative methods. However, it is known that Aβ oligomers and then plaques appear in the brain of patients and cause irreversible damage up to 20 years prior to the onset of symptoms.
Molecular probes which are injected intravenously into the patient and which bind to Aβ oligomers and plaques after crossing the blood/brain barrier could be made visible by means of imaging methods and could thus enable earlier diagnosis of Alzheimer's dementia.
To date, no probes for in-vivo imaging methods exist that bind specifically to pyro-Glu-Aβ species and make the latter visible. Since pyro-Glu-Aβ oligomers play such an important and early role in the disease history, this is precisely what is needed.